Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C31/00—Saturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
  • C07C31/18—Polyhydroxylic acyclic alcohols
  • C07C31/22—Trihydroxylic alcohols, e.g. glycerol
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
  • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
  • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the process of this invention regards the production of tertiary diphenyl carbinols of the formula wherein R is an amino substituted alkyl whose alkyl moiety is a linear or branched aliphatic chain of 1 to 6 carbon atoms and the aminic substituent is a group NHR3 attached to one of the carbon atoms of the alkyl moiety wherein R3 represents hydrogen, a linear or branched alkyl of 1 to 6 carbons, benzyl, phenylethyl, a linear or branched alkylene chain of 1 to 6 carbon atoms connecting the nitrogen atom with one of the carbons of the first alkyl moiety to form a nitrogen containing saturated heterocyclic ring of 5 to 8 members, R1 and R2 each independently represents hydrogen, C1-C4 linear or branched alkyl, C1-C2 alkoxy, fluoro, chloro, or, taken together, represent a methylenedioxy group, and the acid addition salts thereof.
• alkyl moiety are: methyl, ethyl, propyl, isopropyl, butyl, sec.butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3,3-dimethylbutyl, 1,2,2-trimethylpropyl and the like. According to the above definition, one of the carbon of said alkyl moieties must bear a NHR3 as a substituent.
• the radical R3 represents a linear or branched alkylene chain linked to one of the carbons of the first alkyl moiety as defined above
• the first alkyl moiety has two substitutions and the alkylene chain, together with the nitrogen atom and the adjacent portion of the first alkyl moiety, forms a nitrogen containing saturated heterocyclic ring of 5 to 8 members such as pyrrolidine, piperidine, hexahydroazepine and octahydroazocine, which can optionally bear alkyl substituents on the carbon skeleton.
• the length and the number of the alkyl substituents on the carbon skeleton is correlated with the branching of either the portion of the first alkyl moiety or the alkylene chain.
• amino substituted radical R represented in the formula I above are the following:
• the compounds which can be obtained through this process are useful as active ingredients of medicaments and as intermediates for the manufacture thereof.
• active ingredients for medicaments and the intermediates for their production which can be obtained through this process are substances (or intermediates for the manufacture of substances) active on the central nervous system and as antihistaminics.
• substances or intermediates for the manufacture of substances
• Examples of said products and intermediates are described in U.S. 2624739, (C.A. 47 , 11259) U.K. 805511 (C.A. 53 , 12249) and U.S. 2804422, (C.A. 53 , 1558).
• the acid addition salts of the compounds which can be obtained through the process of this invention are all type of acid addition salts with the amine moiety. Therefore, examples of such salts are those with acids which are currently used in the industrial synthetic processes for the isolation of intermediates or final active substances bearing an amino group.
• Representative and suitable acid addition salts of the compounds of formula I include those salts formed by standard reactions with both organic and inorganic acids such as, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, trichloroacetic, succinic, citric, ascorbic, lactic, maleic, fumaric, palmitic, cholic, pamoic, mucic, glutamic, camphoric, glutaric, glycolic, phthalic, tartaric, lauric, stearic, salicylic, methanesulfonic, ethanesulfonic, benzene­sulfonic, sorbic, picric, benzoic, cinnamic and the like.
• organic and inorganic acids such as, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, trichloroacetic, succinic, citric, ascorbic, lactic, male
• a preferred group of acid addition salts of the compounds of formula I are the salts with the anion which are pharmaceutically acceptable, i.e., which can be employed in the pharmaceutical use of the compounds.
• Such acids are hydrochloric, hydrobromic, sulfuric, lactic, maleic, succinic, fumaric, glutaric, citric, malic, p-toluenesulfonic, methanesulfonic, tartaric acid and the like.
• the present invention provides a process for preparing the tertiary diphenyl carbinols containing an aminic substituent of formula I above characterized in that a free acid of the formula R-COOH is contacted with a Grignard reagent of the formula wherein R, R1 and R2 have the same meanings as above and X represents chloro or bromo in an aprotic inert organic solvent or a mixture thereof at a temperature between 20°C and the boiling temperature of the reaction mixture.
• Japanese patent application 7630/58 (Chemical Abstracts, 54 , 2365) teaches the preparation of the same type of compounds by reaction of phenylmagnesium bromide with ethyl-N-benzylisonipecotinate followed by catalytic de-benzylation according to Japanese patent application 930/58.
• Diphenyl-piperidyl-carbinols are prepared by reaction of lower alkyl esters of N-protected isonipecotic acids with phenylmagnesium bromide followed by hydrolysis of the N-protecting group according to U.S. patent 3000896 (C.A 56 , 2439).
• 1,1-Diaryl-2-aminoalkanols falling within the general formula I are prepared by reaction of phenyl-magnesium bromide with 2-amino-hexanoic acid ethyl ester (U.K. 805,511; C.A. 53 , 12249).
• a particular feature of the process of this invention is that it provides very high yields and it does not involve any replacement of the mobile protons of either the carboxylic function and/or the aminic moiety of the reaction substrate R-COOH through formation of masking ester or amide bonds.
• the phenylmagnesium reagents are prepared through common techniques indicated in general text books, such as, for instance: “Methoden der Organischen Chemie", 4th Edition, Vol. XIII/2a, Georg Thieme Verlag, Stuttgart.
• the solvent systems which are used for preparing the Grignard reagents are those usually employed in the art and include lower alkyl ethers, dimethoxymethane, 1,1-dimethoxyethane, 1,2-dimethoxyethane, cyclic ethers like tetrahydrofuran, tetrahydropyran, dioxane, and inert aromatic hydro­carbons such as benzene, toluene and xylene or a mixture thereof.
• the Grignard reagent is usually employed in an amount of 4 to 6 molecular proportions for each molecular proportion of the acid of the formula R-COOH.
• the aminoacid R-COOH is added to the Grignard reagent solution or suspension as such or, if it is a solid, preferably, as a ground powder or a suspension thereof in an inert aprotic solvent which is mixable with that (those) employed for the preparation of the Grignard reagent.
• the solvent for suspending the aminoacid R-COOH is selected among those which are mentioned above for the preparation of the Grignard reagents. Tetrahydrofuran or mixtures of tetrahydrofuran and toluene are the preferred solvents suitable for both the manufacture of the Grinard reagent and the suspension of the aminoacid for the reaction process of this invention.
• the addition of the aminoacid is generally made by keeping the temperature of the reaction mixture between 20°C and 100°C. When the addition is completed, the mixture is heated for 12 to 25 hours at a temperature between 70°C and the boiling temperature of the mixture, preferably between 80°C and 120°C, under stirring.
• an over-pressure of 0.2 to 2.0 atmospheres is created, for instance, by introducing inert gas (e.g. nitrogen) into the reaction vassel, in order to maintain the reaction temperature at the highest values of the above mentioned preferred range.
• inert gas e.g. nitrogen
• the reaction time may be shorter than the interval indicated above, for instance it may vary from 6 to 12 hours.
• the amount of the solvent or mixture of solvents (and, in this latter case, their mutual proportions) used to carry out the process of the invention in general depends on the operative conditions. If the same solvent or mixture of solvents is employed for both the manufacture of the Grignard reagent and the suspension of the aminoacid, in general , it is preferred to have a reaction solvent volume corresponding to from about 5 to about 20 ml of solvent or mixture of solvents for each gram of aminoacid, with the lower amounts of the above range being usually employed when the reaction is carried out under an over-pressure as indicated above.
• the proportions of the solvents when a mixture thereof is employed usually, they may vary within a wide range depending on the specific characteristics of each solvent. In general, with the mixtures tetrahydrofuran: toluene mentioned above, the proportions may vary from 10:1 to 1:10 preferably from 3:1 to 1:3.
• the reaction mixture is poured into an excess of water while concentrate mineral acid (e.g. hydrochloric acid) is added thereto by keeping the pH between 1 and 2.5.
• the temperature during the addition is kept between 0°C and 60°C.
• the mineral acid addition salt of the amino substituted carbinol of formula (I) is recovered from the exhausted reaction mixture through usual separation techniques which, in most cases, consist in the filtration or centrifugation of the precipitated mineral acid addition salt.
• the recovered product is further washed with water or is transformed into a non-salt form or into an acid addition salt with another acid by common procedures.
• the mixture is heated at reflux for a period of 15 to 17 hours, then it is slowly poured into 6-8 liters of cold water. At the same time, concentrated hydrochloric acid (33-36%) is slowly added to the water in order to maintain the pH between 1.5 and 2.5.
• the temperature during the addition is maintained between 0°C and 20°C.
• isonipecotic acid 51.68 g
• isonipecotic acid 51.68 g
• the suspension is refluxed for 16 h.
• the mixture is slowly poured into water (1333 ml) while stirring.
• Concentrated hydrochloric acid is also slowly added in order to maintain the pH between 1 and 2. The temperature is maintained below 20°C with external cooling.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Engineering & Computer Science (AREA)
• Public Health (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Hydrogenated Pyridines (AREA)
• Steroid Compounds (AREA)
• Medicinal Preparation (AREA)
• Other In-Based Heterocyclic Compounds (AREA)
• Pyrrole Compounds (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 1988
  • 1988-03-03 GB GB888805113A patent/GB8805113D0/en active Pending
• 1989
  • 1989-02-06 IE IE37689A patent/IE67632B1/en not_active IP Right Cessation
  • 1989-02-08 EP EP89102130A patent/EP0330875B1/de not_active Expired - Lifetime
  • 1989-02-08 DE DE68923808T patent/DE68923808T2/de not_active Expired - Lifetime
  • 1989-02-08 ES ES89102130T patent/ES2075000T3/es not_active Expired - Lifetime
  • 1989-02-08 AT AT89102130T patent/ATE126507T1/de not_active IP Right Cessation
  • 1989-02-14 ZA ZA891134A patent/ZA891134B/xx unknown
  • 1989-02-24 IL IL89403A patent/IL89403A0/xx unknown
  • 1989-02-27 DK DK198900912A patent/DK174888B1/da not_active IP Right Cessation
  • 1989-02-28 JP JP1045549A patent/JPH023615A/ja active Pending
  • 1989-03-01 CA CA000592387A patent/CA1340055C/en not_active Expired - Fee Related
  • 1989-03-02 HU HU891013A patent/HU209295B/hu unknown
  • 1989-03-02 KR KR89002557A patent/KR960009681B1/ko not_active Expired - Lifetime
• 1995
  • 1995-05-24 US US08/449,027 patent/US5777125A/en not_active Expired - Lifetime
  • 1995-08-31 GR GR950402402T patent/GR3017284T3/el unknown

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